The most common inherited human disorder causing blindness is retinitis pigmentosa, and the most common cause of blindness in persons over the age of 60 is age-related macular degeneration. Blindness in both families of diseases is caused by photoreceptor (PR) cell death. At present, no widely accepted form of therapy exists for these diseases. The long-term objectives of our research program are 1) to elucidate the cellular and genetic mechanisms that lead to PR cell death, and 2) to develop therapeutic means to delay or prevent PR degeneration in hereditary, age-related and environmentally induced retinal degenerations (RDs). One cellular mechanism that may have an important role in PR cell death and offer therapeutic possibilities in RDs is the Unfolded Protein Response (UPR). As proteins are assembled in the endoplasmic reticulum (ER), they must be properly folded to leave the ER. It has long been known that the most common form of autosomal dominant retinitis pigmentosa in the United States is caused by the P23H mutation, and that this mutant protein is misfolded leading to its retention within the ER. Misfolded proteins generate ER stress and activate the UPR signaling pathways. The UPR then upregulates genes, which in turn increase the ER protein folding capacity. If homeostasis cannot be restored, UPR signaling eventually induces cell death by apoptosis. We found that three parallel branches of the UPR, governed by IRE1, ATF6 and PERK, behave significantly differently in time course and that these differences in the duration of their signaling may provide the switch that influences the cell's ultimate fate in response to ER stress. For example, CHOP, a transcription factor induced by the PERK branch of the UPR is sustained and promotes cell death. By contrast, the IRE1 pathway appears to be cytoprotective, and its attenuation is part of the "cell death switch," as sustaining IRE1 signaling in the face of persistent ER stress can result in significantly enhanced cell survival. Thus, modulation of the UPR offers a possibly new avenue for therapy for at least some RDs. There are many RDs that do not appear to result from misfolded proteins, so it is important to know how universal ER stress and UPR signaling are in RDs. We propose to examine this in a number of RDs in native RD models, gene ablation models, as well as by alteration of PR cell death timing by mutant gene dose, environmental manipulation, or modifier genes. Moreover, we will examine the potential therapeutic role of UPR modulation through gene-based methods, to seek combinational therapy with UPR modulation and neuroprotection, and to attempt to develop transgenic mice that would allow real-time, noninvasive assessment of ER stress/UPR signaling in PRs, which would be extremely useful for RD therapeutic research. PUBLIC HEALTH RELEVANCE: More than 6 million people in the United States have blinding diseases with no known cure that result from the death of photoreceptor cells in the eye. The goals of this research program are to study many aspects of one cellular mechanism known as the Unfolded Protein Response that may have an important role in photoreceptor cell death and offer therapeutic possibilities for these diseases.